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Journal ArticleDOI

Gold(III) dithiocarbamate derivatives for the treatment of cancer: solution chemistry, DNA binding, and hemolytic properties.

08 Feb 2006-Journal of Medicinal Chemistry (American Chemical Society)-Vol. 49, Iss: 5, pp 1648-1657
TL;DR: These gold(III) complexes show high reactivity toward some biologically important isolated macromolecules, resulting in a dramatic inhibition of both DNA and RNA synthesis and inducing DNA lesions with a faster kinetics than cisplatin, suggesting that intracellular DNA might not represent their primary or exclusive biological target.
Abstract: Gold(III) compounds are emerging as a new class of metal complexes with outstanding cytotoxic properties and are presently being evaluated as potential antitumor agents. We report here on the solution and electrochemical properties, and the biological behavior of some gold(III) dithiocarbamate derivatives which have been recently proved to be one to 4 orders of magnitude more cytotoxic in vitro than the reference drug (cisplatin) and to be able to overcome to a large extent both intrinsic and acquired resistance to cisplatin itself. Their solution properties have been monitored in order to study their stability under physiological conditions; remarkably, they have shown to undergo complete hydrolysis within 1 h, the metal center remaining in the +3 oxidation state. Their DNA binding properties and ability in hemolyzing red blood cells have been also evaluated. These gold(III) complexes show high reactivity toward some biologically important isolated macromolecules, resulting in a dramatic inhibition of both DNA and RNA synthesis and inducing DNA lesions with a faster kinetics than cisplatin. Nevertheless, they also induce a strong and fast hemolytic effect (compared to cisplatin), suggesting that intracellular DNA might not represent their primary or exclusive biological target.
Citations
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Journal ArticleDOI
TL;DR: The spectrum of gold complexes described as antiproliferative compounds comprises a broad variety of different species including many phosphine complexes as well as gold in different oxidation states.

700 citations

Journal ArticleDOI
TL;DR: Preclinical and clinical investigations showed that the development of new metal agents with modes of action different from cisplatin is possible, and complexes with iron, cobalt, or gold central atoms have shown promising results in preclinical studies and compounds with titanium, ruthenium, or galliumcentral atoms have already been evaluated in phase I and phase II trials.
Abstract: The development of metal complexes with platinum central atoms such as cisplatin or carboplatin had an enormous impact on current cancer chemotherapy. However, the spectrum of cancers that can be treated with platinum agents is narrow and treatment efficacy suffers from side effects and resistance phenomena. These unresolved problems in platinum-based anti-cancer therapy have stimulated increased research efforts in the search for novel non platinum-containing metal species as cytostatic agents. Preclinical and clinical investigations showed that the development of new metal agents with modes of action different from cisplatin is possible. Thus, complexes with iron, cobalt, or gold central atoms have shown promising results in preclinical studies and compounds with titanium, ruthenium, or gallium central atoms have already been evaluated in phase I and phase II trials. This review covers some relevant examples of preclinical and clinical research on novel non platinum metal complexes.

512 citations

Journal ArticleDOI
TL;DR: It is proposed that the relevant cytotoxic actions produced by gold compounds are mainly the result of potent inhibition of thioredoxin reductase; the alterations of mitochondrial functions, elicited by profound TrxR inhibition, would eventually lead to cell apoptosis.

486 citations

Journal ArticleDOI
TL;DR: The use of nonessential metals as probes to target molecular pathways as anticancer agents is also emphasized in this article, where the design of coordination complexes for cancer treatment is reviewed and design strategies and mechanisms of action are discussed.
Abstract: Metals are essential cellular components selected by nature to function in several indispensable biochemical processes for living organisms. Metals are endowed with unique characteristics that include redox activity, variable coordination modes, and reactivity towards organic substrates. Due to their reactivity, metals are tightly regulated under normal conditions and aberrant metal ion concentrations are associated with various pathological disorders, including cancer. For these reasons, coordination complexes, either as drugs or prodrugs, become very attractive probes as potential anticancer agents. The use of metals and their salts for medicinal purposes, from iatrochemistry to modern day, has been present throughout human history. The discovery of cisplatin, cis-[PtII(NH3)2Cl2], was a defining moment which triggered the interest in platinum(II)- and other metal-containing complexes as potential novel anticancer drugs. Other interests in this field address concerns for uptake, toxicity, and resistance to metallodrugs. This review article highlights selected metals that have gained considerable interest in both the development and the treatment of cancer. For example, copper is enriched in various human cancer tissues and is a co-factor essential for tumor angiogenesis processes. However the use of copper-binding ligands to target tumor copper could provide a novel strategy for cancer selective treatment. The use of nonessential metals as probes to target molecular pathways as anticancer agents is also emphasized. Finally, based on the interface between molecular biology and bioinorganic chemistry the design of coordination complexes for cancer treatment is reviewed and design strategies and mechanisms of action are discussed.

423 citations

Journal ArticleDOI
TL;DR: The aim of this review is to highlight specific interactions of metal-based anticancer drugs with the cellular redox homeostasis and to explain this behavior by considering chemical properties of the respective anticancer metal complexes currently either in (pre)clinical development or in daily clinical routine in oncology.
Abstract: Cells require tight regulation of the intracellular redox balance and consequently of reactive oxygen species for proper redox signaling and maintenance of metal (e.g., of iron and copper) homeostasis. In several diseases, including cancer, this balance is disturbed. Therefore, anticancer drugs targeting the redox systems, for example, glutathione and thioredoxin, have entered focus of interest. Anticancer metal complexes (platinum, gold, arsenic, ruthenium, rhodium, copper, vanadium, cobalt, manganese, gadolinium, and molybdenum) have been shown to strongly interact with or even disturb cellular redox homeostasis. In this context, especially the hypothesis of “activation by reduction” as well as the “hard and soft acids and bases” theory with respect to coordination of metal ions to cellular ligands represent important concepts to understand the molecular modes of action of anticancer metal drugs. The aim of this review is to highlight specific interactions of metal-based anticancer drugs with t...

417 citations


Cites background from "Gold(III) dithiocarbamate derivativ..."

  • ...However, several studies suggest that the formed Au-DNA adducts are less stable than that formed by cisplatin (236, 322) presumably because of lower hydrolytic stability (57, 322)....

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References
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Journal ArticleDOI
TL;DR: Estimates can be used to more fully understand the redox biochemistry that results from oxidative stress, which hopefully will provide a rationale and understanding of the cellular mechanisms associated with cell growth and development, signaling, and reductive or oxidative stress.

4,274 citations

Journal ArticleDOI
01 Jan 1952-Analyst
TL;DR: In this article, the potential -volume curve obtained during potentiometric titrations shows only a small potential change at the end-point, and it has been customary to plot a deltaE/deltaV-volume curve and to take the peak of this curve as the equivalent point.
Abstract: When the potential - volume curve obtained during potentiometric titrations shows only a small potential change at the end-point, it has been customary to plot a deltaE/deltaV - volume curve and to take the peak of this curve as the equivalent point. In 1950, the author proposed a method of transforming these curves by a numerical manipulation into straight lines intersecting at the equivalence point. In this article another way of transforming titration curves into straight lines has now been developed. A simple theoretical treatment shows that the method can be applied to titrations involving acids and bases, ionic precipitations, formation of complexes, and oxidation - reduction reactions. To facilitate the use of the method a table has been compiled giving quantities to be calculated and plotted against volume of titrant added. These quantities can be evaluated by simple slide rule calculations and, since straight line relationships hold, end-points can be obtained by simple extrapolation. The practice of the method is applicable to potentiometers calibrated either in millivolts or in pH units, even when titrations other than acid - alkali reactions are in use.

2,757 citations

Journal ArticleDOI

859 citations

Book ChapterDOI
TL;DR: A trinuclear Pt complex with two monofunctional Pt centers has recently been found to exhibit an intriguing new mode of DNA binding and has entered clinical trials, suggesting potential in the anti-HIV field.
Abstract: Publisher Summary Biomedical inorganic chemistry “Elemental Medicine” is an important new area of chemistry. Platinum complexes are now among the most widely used drugs for the treatment of cancer. Three injectable Pt(II) compounds have been approved and several other cis -diam(m)ine complexes are on clinical trials, including an oral Pt(IV) complex. Microbial resistance to established organic antibiotics is a potentially serious problem and provides an impetus for the development of novel antimicrobial metal compounds. With appropriate choice of ligands, it is possible to change the mode of Pt binding to DNA and to circumvent acquired resistance of cancer cells to cisplatin; a trinuclear Pt complex with two monofunctional Pt centers has recently been found to exhibit an intriguing new mode of DNA binding and has entered clinical trials. There is potential in the anti-HIV field. Polyoxometallates of the Keggin type bind to viral envelope sites on cell surfaces and interfere with virus adsorption.

319 citations